Vasoconstrictive substituted aryloxyalkyl diamines

ABSTRACT

The present invention is concerned with compounds having the formula ##STR1## the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein R 1  is hydrogen or C 1-6  alkyl; R 2  is hydrogen or C 1-6  alkyl; R 3  is C 1-6  alkyl, hydroxy, cyano, halo, C 1-6  alkyloxy, aryloxy, arylmethoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkyl-S-, C 1-6  alkyl(S═O)--, C 1-6  alkylcarbonyl; R 4  is hydrogen, halo, hydroxy, C 1-6  alkyl, or C 1-6  alkyloxy; or R 3  and R 4  taken together form a bivalent radical; R 5  and R 6  each independently are hydrogen, halo, hydroxy, C 1-6  alkyl, C 1-6  alkyloxy, aryloxy or arylmethoxy; R 7  is hydrogen; Alk 1  is C 2-5  alkanediyl; Alk 2  is C 2-15  alkanediyl; Q is a heterocyclic ring containing at least one nitrogen atom or a radical of formula ##STR2## Pharmaceutical compositions, preparations and use as a medicine are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT Application Ser. No. PCT/EP 94/02702,filed Aug. 12, 1994, which claims priority from European PatentApplication Ser. No. 93.202.445.8, filed on Aug. 19, 1993; and EuropeanPatent Application Ser. No. 93.202.444.1, filed on Aug. 19, 1993.

The present invention relates to novel substituted aryloxyalkyldiaminederivatives, processes for their preparations, pharmaceuticalcompositions containing them and their use as a medicine, in particularfor the prevention and/or treatment of disorders characterized byexcessive vasodilatation, especially migraine.

Migraine is a non-lethal disease suffered by one in ten individuals. Themain symptom is headache; other symptoms include vomiting andphotophobia. For many years the most widely used treatment for migraineinvolved the administration of ergotalkaloids, which show howeverseveral adverse side effects. Recently a tryptamine derivative, i.e.sumatriptan, was introduced as a novel antimigraine drug. We have nowsurprisingly found that the present novel substituted aryloxyalkyldiamine derivatives show 5-HT₁ -like agonistic activity and can thus beused in the treatment of disorders characterized by excessivevasodilatation, especially migraine.

In Arzneimittel-Forschung, 25, 1404 (1975) some guanidine and amidincderivatives, among which N- 2-2-(2-methoxyphenoxy)ethylamino!ethyl!guanidine, are disclosed as havingnoradrenaline depleting activity.

In EP-0,511,072 derivatives of 2-aminopyrimidine-4-carboxamide havingthe general formula (A) are disclosed as antagonists of α₁ -adrenergicreceptors. ##STR3## The present invention is concerned with compoundshaving the formula ##STR4## the pharmaceutically acceptable acidaddition salts thereof, and the stereochemically isomeric forms thereof,wherein

R¹ and R² each independently are hydrogen or C₁₋₆ alkyl;

R³ is C₁₋₆ alkyl, hydroxy, cyano, halo, C₁₋₆ alkyloxy, aryloxy,arylmethoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkyl-S-, C₁₋₆alkyl(S═O)--, C₁₋₆ alkylcarbonyl;

R⁴ is hydrogen, halo, hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkyloxy; or R³ andR⁴ taken together form a bivalent radical of formula ##STR5## in thesebivalent radicals one or two hydrogen atoms may be substituted with C₁₋₆alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--;

each X independently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--,--NR⁸ --;

n is 3 or 4;

each Y independently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--,--NR⁸ --;

m is 2 or 3;

each Z is --O--C(O)--, --C(O)--O--, --NH--C(O)--, --C(O)--NH--,--O--S(O)₂ --;

t is 1 or 2;

R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--;

R⁵ and R⁶ each independently are hydrogen, halo, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkyloxy, aryloxy or arylmethoxy;

R⁷ is hydrogen;

Alk¹ is C₂₋₅ alkanediyl;

Alk² is C₂₋₁₅ alkanediyl;

Q is a radical of formula ##STR6## wherein R⁹ is hydrogen, cyano,aminocarbonyl or C₁₋₆ alkyl;

R¹⁰ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₆ cycloalkylor arylC₁₋₆ alkyl;

R¹¹ is hydrogen or C₁₋₆ alkyl; or

R¹⁰ and R¹¹ taken together may form a bivalent radical of formula--(CH₂)₄ -- or --(CH₂)₅ --, or a piperazine which is optionallysubstituted with C₁₋₆ alkyl;

R¹², R¹³, R¹⁴, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁶, R³⁷ and R³⁸ each independently are hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆ alkyloxy, aryloxy, C₁₋₆ alkylthio, cyano, amino, mono- ordi(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆ cycloalkyl)-amino, aminocarbonyl,C₁₋₆ alkyloxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, piperidinyl,pyrrolidinyl;

R¹⁵, R¹⁸ and R³⁵ each independently are hydrogen, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, or arylC₁₋₆ alkyl;

q is 1, 2 or 3;

R¹⁶ and R¹⁷ are both hydrogen, or taken together with the carbon atom towhich they are connected form C(O);

r is 1, 2 or 3;

R³⁰ and R³¹ are both hydrogen or taken together with the carbon atom towhich they are connected form C(O);

R³² is hydrogen, halo or C₁₋₆ alkyl;

R³³ is hydrogen and R³⁴ is hydroxy; or R³³ and R³⁴ taken together mayform a bivalent radical of formula (CH₂)₃ or (CH₂)₄ which is optionallysubstituted with C₁₋₆ alkyl; and

aryl is phenyl optionally substituted hydroxy, halo, C₁₋₆ alkyl, C₁₋₆alkyloxy.

All the compounds of formula (I) are deemed novel except for

(a) N- 2- 2-(2-methoxyphenoxy)ethylamino!ethyl!guanidine; and

(b) the compounds of formula (I) wherein R³ is methoxy, ethoxy orisopropyl; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is chloro, fluoro ormethyl; R⁷ is hydrogen; R² is hydrogen or methyl; R¹ is hydrogen; Alk¹is 1,2-ethanediyl or 1,3-propanediyl; Alk² is 1,2-ethanediyl or1,3-propanediyl; Q is a radical of formula (bb), wherein R¹² is hydrogenand R¹³ is 4-aminocarbonyl.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

As used in the foregoing definitions halo defines fluoro, chloro, bromoand iodo; C₁₋₆ alkyl defines straight and branch chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms such as, forexample, methyl, ethyl, propyl, butyl, pentyl, hexyl as well as thebranched isomers thereof; C₃₋₆ alkenyl defines straight and branchchained hydrocarbon radicals containing one double bond and having from3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; andthe carbon atom of said C₃₋₆ alkenyl being connected to a nitrogen atompreferably is saturated, C₂₋₆ alkenyl defines C₃₋₆ alkenyl and the lowerhomologue thereof, i.e. ethenyl; C₃₋₆ alkynyl defines straight andbranch chained hydrocarbon radicals containing one triple bond andhaving from 3 to 6 carbon atoms such as, for example, 2-propynyl,3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-hexynyl, and the like;and the carbon atom of said C₃₋₆ alkynyl radical beong connected to anitrogen atom preferably is saturated; C₂₋₆ alkynyl defines C₃₋₆-alkynyl and the lower homologue thereof, i.e. ethynyl; C₃₋₆ cycloalkylis generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C₂₋₅alkanediyl defines bivalent straight and branch chained saturatedhydrocarbon radicals having from 2 to 5 carbon atoms such as, forexample, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl and the like; C₂₋₁₅ -alkanediyl defines bivalentstraight and branch chained saturated hydrocarbon radicals having from 2to 15 carbon atoms such as, for example, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl,1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl,1,11-undecanediyl, 1,12-dodecanediyl, 1,13-tridecanediyl,1,14-tetradecanediyl, 1,15-pentadecanediyl, and the branched isomersthereof. The term "C(O)" refers to a carbonyl group.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, ethanedioic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration; C₂₋₆-alkenyl radicals may have the E- or Z-configuration. Stereochemicallyisomeric forms of the compounds of formula (I) are obviously intended tobe embraced within the scope of this invention.

R¹ is suitably hydrogen or methyl, preferably R¹ is hydrogen;

R² is suitably hydrogen or methyl, preferably R² is hydrogen;

R³ is suitably C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy, arylmethoxy,preferably R³ is methyl, ethyl, hydroxy, methoxy, ethoxy orphenylmethoxy;

R⁴ is suitably hydrogen, C₁₋₆ alkyl or C₁₋₆ alkyloxy, preferably R⁴ ishydrogen or methoxy;

or when taken together

R³ and R⁴ form suitably a bivalent radical for formula (a), (b), (e),(f), (g) or (h);

each X is suitably O or S, preferably each X is O;

each Y is suitably O or S, preferably each Y is O;

each Z is suitably --O--C(O)--, --C(O)--O--;

R⁸ is suitably hydrogen or C₁₋₆ alkyl; preferably

R⁸ is hydrogen or methyl;

R⁵ is suitably hydrogen or C₁₋₆ alkyl, preferably R⁵ is hydrogen ormethyl;

R⁶ is suitably hydrogen or C₁₋₆ alkyl, preferably R⁶ is hydrogen ormethyl;

Alk¹ is suitably C₂₋₃ alkanediyl, preferably Alk¹ is 1,2-ethanediyl,1,2-propanediyl or 1,3-propanediyl;

Alk² is suitably C₂₋₆ alkanediyl, preferably Alk² is 1,3-propanediyl or1,4-butanediyl;

Q is preferably a radical of formula (aa), (bb) or (dd);

R⁹ is suitably hydrogen, cyano, aminocarbonyl or methyl, preferably R⁹is hydrogen or cyano;

R¹⁰ is suitably hydrogen or C₁₋₆ alkyl, preferably R¹⁰ is hydrogen,methyl or ethyl;

R¹¹ is suitably hydrogen or C₁₋₆ alkyl, preferably R¹¹ is hydrogen ormethyl;

R¹² and R¹³ each independently are suitably hydrogen, hydroxy, halo ormethyl, preferably both R¹² and R¹³ are hydrogen or R¹² is hydrogen andR¹³ is hydroxy;

R¹⁴ is suitably hydrogen or hydroxy, preferably R¹⁴ is hydrogen;

R¹⁵ is suitably hydrogen or phenylmethyl, preferably R¹⁵ is hydrogen;

q is preferably 2;

R¹⁶ and R¹⁷ is are both preferably hydrogen;

R¹⁸ is suitably hydrogen or phenylmethyl, preferably R¹⁸ is hydrogen;

R¹⁹ is suitably hydrogen, halo or methyl, preferably R¹⁹ is hydrogen orchloro;

R²⁰ and R²¹ each independently suitably are hydrogen, halo or methyl,preferably R²⁰ and R²¹ are hydrogen or chloro;

R²² and R²³ each independently suitably are hydrogen, hydroxy, chloro ormethyl, preferably R²² and R²³ are both hydrogen or R²² is hydrogen andR²³ is hydroxy;

R²⁴ and R²⁵ each independently suitably are hydrogen, hydroxy, halo ormethyl, preferably R²⁴ and R²⁵ are both hydrogen or R²⁴ is hydrogen andR²⁵ is chloro;

R²⁶ and R²⁷ each independently suitably are hydrogen, halo, C₁₋₆alkyloxy, C₁₋₆ alkylthio, amino, mono- or di(C₁₋₆ alkyl)amino;preferably R²⁶ is hydrogen, chloro, methylthio or amino and R²⁷ ishydrogen;

R²⁸ and R²⁹ each independently suitably are hydrogen, halo, C₁₋₆ alkyl,preferably R²⁸ and R²⁹ are hydrogen or chloro;

r preferably is 2;

R³⁰ and R³¹ both preferably are hydrogen;

R³² is suitably hydrogen or methyl, preferably R³² is hydrogen; and

aryl is preferably phenyl.

Special compounds of formula (I) are those compounds of formula (I)wherein wherein R³ is C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy, aryloxy,arylmethoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl; one of R⁴, R⁵ and R⁶ ishydrogen and the others each independently are hydrogen, halo, hydroxy,C₁₋₆ alkyl, or C₁₋₆ alkyloxy, Q is a radical of formula (aa), (bb),(cc), (dd), (ee) wherein R³⁸ is hydrogen, (ff), (gg), (hh), (ii), (jj),(kk), (ll).

Other special compounds of formula (I) are those compounds of formula(I) wherein

R³ and R⁴ taken together form a bivalent radical of formula ##STR7## inthese bivalent radicals one or two hydrogen atoms may be substitutedwith C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkylsulfoxyl; and whereinX, Y, Z, m, n, and t are defined as in claim 1; and Q is a radical offormula (aa), (bb), (cc), (dd), (ee) wherein R³⁸ is hydrogen, (ff),(gg), (hh), (ii), (jj), (kk), (ll).

Interesting compounds are those compounds of formula (I), wherein R¹ andR² both are hydrogen.

An interesting subset of compounds are those compounds of formula (I),wherein R³ and R⁴ taken together do not form a bivalent radical andwherein R³ is C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy or arylmethoxy,especially methyl, hydroxy, methoxy, ethoxy and phenylmethoxy.

Further interesting compounds are those compounds of formula (I) whereinR⁴ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkyloxy and R⁵ is hydrogen or C₁₋₆alkyloxy.

Particular compounds are those compounds of formula (I) wherein Q is aradical of formula (aa), (bb) or (dd), especially (bb) or (dd).

Particularly interesting compounds are those interesting compounds,wherein Q is a radical of formula of (bb), wherein R⁹ and R¹⁰ arehydrogen.

Another group of particularly interesting compounds are thoseinteresting compounds wherein Q is a radical of formula (dd), wherein qis 2, R¹⁶ and R¹⁷ are hydrogen and R¹⁸ is hydrogen.

Another interesting subset of compounds are those compounds of formula(I), wherein R³ and R⁴ taken together form a bivalent radical of formula(a), (b), (e), (f), (g) or (h);

Particular compounds are those compounds of formula (I) wherein Q is aradical of formula (aa), (bb) or (dd), especially (bb) or (dd).

Particularly interesting compounds are those interesting compounds,wherein Q is a radical of formula (bb), wherein R¹² and R¹³ arehydrogen.

Another group of particularly interesting compounds, wherein Q is aradical of formula (dd), wherein q is 2, R¹⁵ and R¹⁶ are hydrogen andR¹⁷ is hydrogen.

Preferred compounds are:

N- 2-(2,3-dimethoxyphenoxy)ethyl!-N'-2-pyrimidinyl-1,3-propanediamine;

2- 2- 3-(2-pyrimidinylamino)propyl!amino!ethoxy!phenol; N-2-(2,3-dimethoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;

N-2-(2-methoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-2-(2-ethoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-3-(2-methoxyphenoxy)propyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-2-pyrimidinyl-1,3-propanediamine;N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;

N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,4-butanediamine;N-2-(1-naphthalenyloxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine,the pharmaceutically acceptable acid addition salt thereof or thestereochemically isomeric forms thereof.

The compounds of formula (I) can generally be prepared by reacting adiamine of formula (II) with a reagent of formula (III) wherein W¹ is areactive leaving group such as, for example, halo, e.g. chloro, bromo;alkyloxy, e.g. methoxy, ethoxy and the like; aryloxy, e.g. phenoxy andthe like; alkylthio, e.g. methylthio, ethylthio and the like; arylthio,e.g. benzenethio and the like.

In the formulas (II), (III) and all the following formulas the variablesR¹, R², R³, R⁴, R⁵, R⁶, R⁷, Alk¹, Alk², and Q are as defined underformula (I), unless indicated otherwise. ##STR8##

Said reaction can be performed by stirring the diamine of formula (II)with the reagent of formula (III) in an appropriate solvent such as, forexample, an alcohol, e.g. ethanol and the like; a halogenatedhydrocarbon, e.g. trichloromethane and the like or an ether, e.g.tetrahydrofuran and the like; an aromatic hydrocarbon, e.g.methylbenzene and the like; or mixtures thereof. Optionally a base suchas, for example, an alkalimetal carbomate, e.g. sodium or potassiumcarbonate; and alkalimetal hydrogen carbonate, e.g. sodium or potassiumhydrogen carbonate; an appropriate organic base, e.g.N,N-diethylethanamine, pyridine and the like bases, can be added to pickup the acid that may be formed during the course of the reaction.Elevated temperatures may enhance the rate of the reaction. Preferablythe reaction is performed at the reflux temperatures of the reactionmixture.

The compounds of formula (I) can also generally be prepared by reductiveN-alkylation of an aminoderivative of formula (VI) with an appropriatealdehyde of formula (V), wherein Alk³ is C₁₋₄ alkanediyl. ##STR9##

Said reaction is performed by stirring the reactants of formula (V) and(VI) in an appropriate solvent such as, for example, an alcohol, e.g.ethanol and the like; an ether, e.g. tetrahydrofuran and the like; anaromatic solvent, e.g. methylbenzene and the like, or mixtures thereof.Optionally a water separator can be used to remove the water that isformed during the course of the reaction. The resulting imine can thenbe reduced by reactive hydride reagents such as, for example, sodiumborohydride, or by catalytic hydrogenation on an appropriate catalystsuch as, for example, palladium on charcoal, platinum on charcoal, Raneynickel and the like in a suitable solvent such as, for example analcohol, e.g. methanol, ethanol and the like; an ether, e.g.tetrahydrofuran and the like; a carboxylic ester, e.g. ethyl acetate,butyl acetate and the like; or a carboxylic acid, e.g. acetic acid,propanoic acid and the like. Optionally the reaction may be performed atelevated temperatures and/or pressures.

The intermediate aldehyde of formula (V) can be prepared by reducing anacyl derivative of formula (IV) wherein Alk³ is defined as above. Inturn said acyl halide can be prepared by reacting the corresponding,with a halogenating reagent such as thionylchloride, phosphorustrichloride, phosphorus tribomide, oxalylchloride and the like. Thelatter reaction may be performed in an excess of the halogenatingreagent or in appropriate solvents such as, for example, halogenatedhydrocarbons, e.g. dichloromethane, trichloromethane and the like;aromatic hydrocarbons, e.g. methylbenzene and the like; ethers, e.g.tetrahydrofuran, 1,4-dioxane and the like, or dipolar aprotic solvents,e.g. N,N-dimethylformamide, N,N-dimethylacetamide and the like. Stirringand elevated temperatures may be appropriate to enhance the rate of thereaction.

Said reduction of the acylhalide of formula (IV) can for instance beperformed by catalytic hydrogenation with a catalyst such as palladiumon charcoal, palladium on bariumsulfate, platinum on charcoal and thelike in appropriate solvents such as, for example, ethers, e.g.tetrahydrofuran and the like; preferably in admixture with a dipolaraprotic solvent such as, for example, N,N-dimethylformamide,N,N-dimethylacetamide and the like. Optionally a catalyst poison can beadded such as thiophene, quinoline-sulfur and the like. The reactionsequence starting from the intermediate of formula (IV) and yieldingcompounds of formula (I) may be performed as a one-pot procedure.

The compounds of formula (I) can also be prepared by N-alkylating anamine of formula (VI) with an intermediate of formula (VII), wherein W²is a reactive leaving group such as, for example, halo, e.g. chloro,bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy,methylbenzenesulfonyloxy and the like, in appropriate solvents such asketones, e.g. 2-butanone and the like; ethers, e.g. tetrahydrofuran andthe like; aromatic hydrocarbons, e.g. methylbenzene and the like;dipolar aprotic solvents, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide and the like. ##STR10##

Stirring and heating may enhance the reaction rate. Optionally asuitable base may be added to pick up the acid that is formed during thecourse of the reaction such as, for example an alkali metal carbonate,e.g. sodium or potassium carbonate; an alkali metal hydrogen carbonate,e.g. sodium or potassium hydrogen carbonate and the like; an appropriateorganic base, e.g. N,N-diethylethanamine, pyridine and the like.

The compounds of formula (I), can also be convened into each other byfunctional group transformations. For instance the compounds of formula(I), wherein Q represents a pyrimidinyl moiety can be converted intotheir tetrahydroanalogs following art-known catalytic hydrogenationprocedures. ##STR11## Furthermore, compounds of formula (I) bearing aC₂₋₆ alkynyl group or C₂₋₆ alkenyl group can be converted into thecorresponding compounds bearing C₁₋₆ alkyl group following art-knownhydrogenation techniques.

Compounds of formula (I) bearing a cyano group can be converted into thecorresponding compounds beating an aminomethyl substituent followingart-known hydrogenation techniques.

Compounds bearing an alkyloxy substituent can be converted intocompounds bearing a hydroxy group by treating the alkyloxy compound withan appropriate acidic reagent such as for example, hydrohalic acid, e.g.hydrobromic acid or borontribromide and the like.

Compounds bearing a arylmethoxy substituent may be converted intocompounds bearing a hydroxy substituent following art-knowndebenzylation reactions such as, for example, hydrogenolysis.

Compounds bearing an amino substituent can be N-acylated or N-alkylatedfollowing art-known N-acylation or N-alkylation procedures.

Compounds bearing a thio-substituent may be oxidised to thecorresponding sulfinyl derivatives.

Some of the intermediates mentioned hereinabove are art-known, othersare novel and can be prepared following art-known methodologies.

Pure stereochemically isomeric forms of the compounds of this inventionmay be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. liquidchromatography. Enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

The compounds of formula (I), the pharmaceutically acceptableacid-addition salts and stereochemically isomeric forms thereof haveinteresting pharmacological properties: they show 5HT_(1-like) agonisticactivity. The compounds of the present invention have remarkablevasoconstrictor activity. They are useful to treat conditions which arerelated to vasodilatation. For instance, they are useful in thetreatment of conditions characterized by or associated with cephalicpain, e.g. cluster headache and headache associated with vasculardisorders, especially migraine. These compounds are also useful in thetreatment of venous insufficiency and in the treatment of conditionsassociated with hypotension. The vasoconstrictor activity of thecompounds of formula (I) can be determined using the test described inthe pharmacological example, wherein the serotonin-like response of thecompounds of the present invention was tested on the basilar arteries ofpigs.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs and solutions:or solid carders such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, to aidsolubility for example, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment It isespecially advantageous to formulate the aforementioned pharmaceuticalcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used in the specification andclaims herein refers to physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

The compounds of the present invention therefore may be used asmedicines in conditions related to vasodilatation, more in particularhypotension, venous insufficiency and especially cephalic pain amongwhich especially migraine. The compounds of the present invention alsoprovide a method of treating warm-blooded animals suffering fromconditions related to vasodilatation such as, hypotension, venousinsufficiency and especially cephalic pain among which migraine byadministering an effective amount of a compound of formula (I), apharmaceutically acceptable acid addition salt or a stereoisomeric formthereof. Those skilled in the art could easily determine the effectiveamount from the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 1 μg/kg to 1 mg/kgbody weight, and in particular from 2 μg/kg to 200 μg/kg body weight. Itmay be appropriate to administer the required dose as two, three, fouror more sub-doses at appropriate intervals throughout the day. Saidsub-doses may be formulated as unit dosage forms, for example,containing 0.005 to 20 mg, and in particular 0.1 mg to 10 mg of activeingredient per unit dosage form.

The following examples are intended to illustrate and not to limit thescope of the present invention in all its aspects.

EXPERIMENTAL PART A. Preparation of the intermediates Example 1

a) 2-bromo-1,1-diethoxyethane (0.097 mol) was added to a mixture of2,3-dimethoxyphenol (0.097 mol) and potassium carbonate (0.097 mol) inN,N-dimethylacetamide (200 ml). The reaction mixture was stirred for 24hours at 140° C. The solvent was evaporated. The residue was partitionedbetween 1,1'-oxybisethane and a solution of NaOH in water. The organiclayer was separated, washed with a saturated NaCl solution, dried(MgSO₄), filtered and the solvent was evaporated, yielding 23 g (87.7%)of 1-(2,2-diethoxyethoxy)-2,3-dimethoxybenzene (interm. 1).

b) Hydrochloric acid (2N) (125 ml) was added to a solution ofintermediate (1) (0.078 mol) in 2-propanone (200 ml). The reactionmixture was stirred for 15 minutes at 60° C. The organic solvent wasevaporated. Water (300 ml) was added. This mixture was extracted with1,1'-oxybisethane (3×200 ml). The separated organic layer was washedwith a saturated NaCl solution, dried (MgSO₄), filtered and the solventwas evaporated, yielding 11.6 g (76%) of2-(2,3-dimethoxyphenoxy)acetaldehyde (interm.2). In a similar mannerwere also prepared:

2- 2-(phenylmethoxy)phenoxy!acetaldehyde (interm. 3);

2-(methylthio)phenoxy!acetaldehyde (interm. 4); and

2-(methylsulfinyl)phenoxy!acetaldehyde (interm. 5).

Example 2

A mixture of N- 2-(2-methoxyphenoxy)ethyl!aminepropanenitrile (0.035mol) in methanol (500 ml) was hydrogenated with Raney nickel (2 g) as acatalyst. After uptake of hydrogen (2 eq.), the catalyst was filteredoff and the filtrate was evaporated, yielding 7.8 g (99.4%) of product.A sample (1.0 g) was dissolved in 2-propanol and converted into thehydrochloric acid salt (1:2). The salt was filtered off and dried,yielding 0.81 g (60.8%) of N-2-(2-methoxyphenoxy)ethyl!-1,3-propanediamine dihydrochloride; mp.149.4° C. (interm. 6).

Example 3

a) A mixture of 8-methoxy-1,2-benzoxathiin, 2,2-dioxide (0.020 mol) in ahydrobromic acid solution 48% in water (450 ml) was stirred and refluxedfor 2 hours. The reaction mixture was cooled. The resulting precipitatewas filtered off and the filtrate was extracted with diethyl ether. Theseparated organic layer was dried (MgSO₄), filtered and the solvent wasevaporated, yielding: 37.4 g 1,2-benzoxathiin-8-ol, 2,2-dioxide (94.4%)(interm.7).

b) A mixture of intermediate 7 (0.13 mol), 2-bromoethanol (0.39 mol) andpotassium carbonate (0.015 mol) in 2-propanone (50 ml) was stirred andrefluxed overnight. The mixture was cooled and the resulting precipitatewas faltered off. The filtrate was evaporated and the residue wascrystallized from CH₂ Cl₂. The precipitate was filtered off and thefiltrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97.5/2.5). Thepure fractions were collected and the solvent was evaporated, yielding:3.1 g (9.8%) of 2-(1,2-benzoxathiin-8-yloxy)ethanol 2,2-dioxide(interm.8)

c) N,N,diethylethanamine (10 ml) was added dropwise to a mixture ofintermediate 8 (0.089 mol) and methanesulfonyl chloride (0.13 mol) in2-propanone (250 ml), stirred and cooled on an ice bath. The reactionmixture was stirred for 1 hour at room temperature. The mixture wasfiltered and the filtrate was evaporated. The residue was dissolved inCH₂ Cl₂. The organic solution was washed with an aqueous hydrochloricacid solution, dried (MgSO₄), filtered and the solvent was evaporated.The residue was crystallized from CH₂ Cl₂. The precipitate was filteredoff and dried (vacuum; 70° C.), yielding 15.6 g (54.7%)2-(1,2-benzoxathiin-8-yloxy)ethanol 2,2-dioxide methanesulfonate(ester); mp. 117° C. (interm. 9).

d) A mixture of intermediate 9 (0.019 mol) in methanol (250 ml) washydrogenated with palladium-on-charcoal catalyst (2 g) as a catalyst.After uptake of hydrogen (H₂) (1 equiv), the catalyst was filtered offand the filtrate was evaporated. The residue was crystallized from CH₃CN. The precipitate was filtered off and dried (vacuum; 60° C.),yielding: 3.1 g (50.6%) 2-(3,4-dihydro-1,2-benzoxathiin-8-yl)oxy!ethanol methanesulfonate(ester)2,2-dioxide; mp. 155° C. (interm. 10)

Example 4

a) A mixture of 2,3-dihydro-5-hydroxy-1,4-benzodioxin (0.13 mol),2-bromo-1,1-diethoxyethane (0.13 mol) and potassium carbonate (0.13 mol)in N,N-dimethylacetamide (250 ml) was stirred overnight at 140° C. Thesolvent was evaporated. The residue was partitioned between1,1'-oxybisethane and water. The organic layer was separated, washedwith a saturated NaCl solution, dried (MgSO₄), filtered and the solventwas evaporated. The residual oil was crystallized from2,2'-oxybispropane. The precipitate was filtered off and dried, yielding21 g (60.2%) 5-(2,2-diethoxyethoxy)-2,3-dihydro-1,4-benzodioxin; mp.73.1° C. (interm. 11).

b) Hydrochloric acid 2N (125 ml) was added to a solution of intermediate(R 97.205) (0.078 mol) in 2-propanone (200 ml). The reaction mixture wasstirred for 15 minutes at 60° C. The organic solvent was evaporated (40°C.). Water (300 ml) was added. This mixture was extracted withdichloromethane. The separated organic layer was dried (MgSO₄), filteredand the solvent was evaporated, yielding 13 g (86.6%) of(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!acetaldehyde (interm.12).

                  TABLE 1                                                         ______________________________________                                        In this manner were prepared:                                                  ##STR12##                                                                    Int. no.       R.sup.3, R.sup.4                                               ______________________________________                                        12             O(CH.sub.2).sub.2 O                                            13             (CH.sub.2).sub.4                                               14             OCHCH                                                          15             O(CH.sub.2).sub.3                                              16             (CH.sub.2).sub.3 O                                             17             C(CH.sub.3)C(CH.sub.3)O                                        ______________________________________                                    

B. Preparation of the final compounds Example 5

A mixture of intermediate 6 (0.03 mol), 2-chloropyrimidine (0.03 mol)and sodium carbonate (0.03 mol) in ethanol (150 ml) was stirred andrefluxed overnight. The reaction mixture was filtered over dicalite. Thefiltrate was evaporated. The residue was dissolved in acetonitrile andthis mixture was acidified with HCl/2-propanol. The precipitate wasfiltered off. The filtrate was evaporated and the residue was stirred inwater. This mixture was alkalized with NaOH, then extracted with1,1'-oxybisethane. The separated organic layer was dried (MgSO₄),filtered and the solvent was evaporated. The residue was dissolved inwarm methanol (500 ml) and converted into the ethanedioic acid salt(1:2) with a solution of ethanedioic acid (Sg) in methanol. The salt wasfiltered off and dried, yielding 6.8 g (56.3%) of N-2-(2-methoxyphenoxy)ethyl!-N'-2-pyrimidinyl-1,3-propanediamineethanedioate (1:2); mp. 178.4° C. (comp. 1).

Example 6

N-2-pyrimidinyl-1,3-propanediamine (0.042 mol) was added to a solutionof intermediate 2 (0.056 mol) in ethanol (200 ml) and this mixture wasstirred for 30 min. at room temperature. The reaction mixture was cooledto 0° C. with an ice salt bath. Sodium borohydride (0.059 mol) was addedand the reaction mixture was stirred for 30 minutes at 0° C., then for 1hour at room temperature. A small mount of water was added and thesolvent was evaporated at 40° C. The residue was partitioned betweendichloromethane and water. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residual oil (13g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂ /(CH₃ OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated. The residual oil (8 g) was dissolved in2-propanone and converted into the ethanedioic acid salt (1:1). Theprecipitate was filtered off and crystallized from methanol. Theprecipitate was filtered off and dried, yielding 6.7 g (37.8%) of N-2-(2,3-dimethoxyphenoxy)ethyl!-N'-2-pyrimidinyl-1,3-propanediamineethanedioate(1:1); mp. 200.0° C. (comp. 2).

Example 7

a) A mixture of intermediate 3 (0.117 mol) andN-2-pyrimidinyl-1,3-propanediamine (0.087 mol) in ethanol (500 ml) wasstirred for 45 minutes at 20° C. The reaction mixture was cooled to 0°C. (ice salt bath). Sodium borohydride (0.125 mol) was added in oneportion and the reaction mixture was stirred for 2 hours. Water wasadded and the solvent was evaporated. The residue was partitionedbetween 1,1'-oxybisethane and water. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃)95/5). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from 2-propanol. The precipitate wasfiltered off and dried, yielding 7.7 g (23.4%) of N- 2-2-(phenylmethoxy)phenoxy!ethyl!-N'-2-pyrimidinyl-1,3-propanediamine; mp.90.1° C. (comp. 3).

b) A mixture of compound (97232) (0.02 mol) in methanol (250 ml) washydrogenated with palladium on activated carbon 10% (2 g) as a catalyst.After uptake of hydrogen (1 eq.), the catalyst was filtered off. Thefiltrate was evaporated. The residue was dissolved in ethanol andconverted into the hydrochloric acid salt (1:2) with HCl/2-propanol. Thesalt was filtered off and dried, yielding 4.8 g (66.4%) of 2- 2-3-(2-pyrimidinylamino)propyl!amino!ethoxy!phenol dihydrochloride; mp.166.4° C. (comp. 4).

Example 8

A mixture of 1-bromo-3-(2-methoxyphenoxy)propane (0.020 mol),N-2-pyrimidinyl-1,3-propanediamine (0.020 mol) and potassium carbonate(0.03 mol) in N,N-dimethylacetamide (50 ml) was stirred for 48 hours at70° C. The solvent was evaporated. The residue was partitioned betweendichloromethane and water. The organic layer was separate& dried(MgSO₄), filtered and the solvent was evaporated. The residual oil waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃OH/NH₃) 95/5). The desired fractions were collected and the solvent wasevaporated. The residue (5 g) was dissolved in 2-propanone and convenedinto the ethanedioic acid salt (1:1). The precipitate was filtered offand crystallized from methanol. The precipitate was filtered off anddried, yielding 3.41 g of product. This fraction was recrystallized frommethanol. The precipitate was filtered off and dried, yielding 3.3 g(40.6%) N-3-(2-methoxyphenoxy)propyl!-N'-2-pyrimidinyl-1,3-propanediamineethanedioate(1:1); mp. 186.3° C. (comp. 5).

Example 9

A mixture of compound 2 (0.0135 mol) and ethanedioic acid dihydrate(0.0135 mol) in 2-methoxyethanol (300 ml) was hydrogenated at 80° C.with palladium on activated carbon 10% (2 g) as a catalyst in thepresence of a 4% solution of thiophene (2 ml). After uptake of hydrogen(2 eq.), the catalyst was filtered off and the filtrate was evaporated.The residue was crystallized from methanol. The precipitate was filteredoff and dried, yielding 2.56 g (36.7%) of N-2-(2,3-dimethoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamineethanedioate (1:2); mp. 181.1° C. (comp. 6).

Example 10

N-2-pyrimidinyl-1,3-propanediamine (0.05 mol) was added to a solution ofintermediate 12 (0.067 mol) in ethanol (200 ml) and this mixture wasstirred for 30 minutes at room temperature. The reaction mixture wascooled to 0° C. with an ice salt bath. Sodium borohydride (0.070 mol)was added and the reaction mixture was stirred for 30 minutes at 0° C.,then for 30 minutes at room temperature. A small amount of water wasadded and the solvent was evaporated. The residue was partitionedbetween dichloromethane and water. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The residual oilwas purified by column chromatography over silica gel (eluent: CH₂ Cl₂/(CH₃ OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated. The residual oil was dissolved in 2-propanoneand converted into the ethanedioic acid salt (1:2). The precipitate wasfiltered off and crystallized from methanol. The precipitate wasfiltered off and dried, yielding 6 g (23.5%) of N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-2-pyrimidinyl-1,3-propanediamineethane-dioate (1:1); mp. 213.2° C. (comp.7).

Example 11

A mixture of 5-(3-chloropropoxy)-2,3-dihydro-1,4-benzodioxin (0.017mol), N-2-pyrimidinyl-1,3-propanediamine (0.026 mol) and calcium oxide(5 g) in tetrahydrofuran (150 ml) was stirred overnight at 160° C.(pressure vessel). The mixture was cooled, filtered and the filtrate wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃)95/5). The pure fractions werecollected and the solvent was evaporated, yielding 2.66 g N- 3-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!propyl!-N'-2-pyrimidinyl-1,3-propanediamineethanedioate(1:1) (36.0%); mp. 200.2° C. (comp. 8)

Example 12

Compound 7 (0.0078 mol) and ethanedioic acid dihydrate (0.0078 mol) weredissolved in a warm mixture of 2-methoxyethanol (200 ml) and water (100ml). This solution was hydrogenated at 80° C. with palladium onactivated carbon (10%) (2 g) as a catalyst in the presence of a 4%thiophene solution (1 ml). After uptake of hydrogen (2 eq.), thecatalyst was filtered off and the filtrate was evaporated. The residuewas crystallized from methanol. The precipitate was filtered off anddried. This fraction was recrystallized from water. The precipitate wasfiltered off and dried, yielding 0.8 g of product. This fraction wasrecrystallized from methanol/water (5/1). The precipitate was filteredoff and dried, yielding 0.5 g (13.7%) of N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamineethanedioate(2:3); mp. 231.1° C. (comp.9).

Example 13

phenoxy-1-(1methylethyl)methylene!cyanamide (0.019 mol) was added to asolution of N-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-1,4-propanediamine (0.019mol) in methanol (100 ml). The reaction mixture was stirred for 4 daysat room temperature. The solvent was evaporated. The resultant oil waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 90/10). The pure fractions were collected and the solvent wasevaporated. The resultant oil (2.9 g) was crystallized from CH₃ CN. Theprecipitate was filtered off and dried, yielding: 2.4 g (34.9%)N"-cyano-N- 3- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!amino!propyl!-N'-(1-methylethyl)guanidine;mp. 120.6° C. (comp. 10).

Example 14

A mixture of compound 10 (0.003 mol) in hydrochloric acid in 2-propanol(10 ml) and methanol (50 ml) was stirred and refluxed for 30 minutes.The solvent was evaporated. The residue was crystallized from CH₃ CN.The precipitate was filtered off and dried, yielding: 0.53 g (39.1%) ofN- 3- 2- (2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!amino!propyl!amino!(1-methylethyl)amino!methylene!urea dihydrochloride; mp. 155.0° C.(comp. 11).

In this manners were prepared:

                                      TABLE 2                                     __________________________________________________________________________     ##STR13##                                                                    Co. No.                                                                           Ex. No.                                                                           Alk.sup.1                                                                            R.sup.3 R.sup.4, R.sup.6                                                                    physical data                                    __________________________________________________________________________     1  5   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             H     mp. 178.4° C./.2(COOH).sub.2               2  6   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             3OCH.sub.3                                                                          mp. 200.0° C./.(COOH).sub.2                3   7a (CH.sub.2).sub.2                                                                     OCH.sub.2 C.sub.6 H.sub.5                                                             H     mp. 90.1° C.                               4   7b (CH.sub.2).sub.2                                                                     OH      H     mp. 166.4° C./.2HCl                        5  8   (CH.sub.2).sub.3                                                                     OCH.sub.3                                                                             H     mp. 186.3° C./.(COOH).sub.2               12  6   CH(CH.sub.3)CH.sub.2                                                                 OCH.sub.3                                                                             H     mp. 167.9° C./.2HCl                       13  6   (CH.sub.2).sub.2                                                                     CH.sub.3                                                                              H     mp. 204.8° C./.(COOH).sub.2               14  6   (CH.sub.2).sub.2                                                                     OCH.sub.2 CH.sub.3                                                                    H     mp. 160.3° C./.2(COOH).sub.2              15  6   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             5CH.sub.3                                                                           mp. 197.2° C./.(COOH).sub.2               16  8   (CH.sub.2).sub.2                                                                     COCH.sub.3                                                                            H     mp. 179.0° C./(COOH).sub.2                17  6   (CH.sub.2).sub.2                                                                     SCH.sub.3                                                                             H     mp. 217.6° C./(COOH).sub.2                18  8   (CH.sub.2).sub.2                                                                     CN      H     mp. 185.1° C./(COOH).sub.2                19  6   (CH.sub.2).sub.2                                                                     SOCH.sub.3                                                                            H     mp. 177.7° C./2(COOH).sub.2               20  8   (CH.sub.2).sub.2                                                                     Br      H     mp. 198.2° /(COOH).sub.2                  __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR14##                                                                    Co. No.                                                                           Ex. No.                                                                           Alk.sup.1                                                                            R.sup.3 R.sup.4, R.sup.6                                                                    physical data                                    __________________________________________________________________________     6  9   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             3OCH.sub.3                                                                          mp. 181.1° C./.2(COOH).sub.2              21  9   (CH.sub.2).sub.2                                                                     CH.sub.3                                                                              H     mp. 170.3° C./.2HCl                       22  9   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             H     mp. 159.1° C./.2(COOH).sub.2              23  9   (CH.sub.2).sub.2                                                                     OCH.sub.2 CH.sub.3                                                                    H     mp. 168.1° C./.2(COOH).sub.2              24  9   (CH.sub.2).sub.2                                                                     OCH.sub.3                                                                             5CH.sub.3                                                                           mp. 182.8° C./.2(COOH).sub.2              25  9   (CH.sub.2).sub.2                                                                     OH      H     mp. 185.4° C./.2HCl                       26  9   (CH.sub.2).sub.3                                                                     OCH.sub.3                                                                             H     mp. 155.1° C./.2(COOH).sub.2              27  9   (CH.sub.2).sub.2                                                                     COCH.sub.3                                                                            H     mp. 150.6° C./2(COOH).sub.2                                            1/2 H.sub.2 O                                    28  9   (CH.sub.2).sub.2                                                                     CN      H     mp. 188.6° C./3/2(COOH).sub.2             __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR15##                                                                    Co. No.                                                                           Ex. No                                                                            R.sup.3, R.sup.4                                                                           Alk.sup.1                                                                         Alk.sup.2                                                                         Physical data                                    __________________________________________________________________________     7  10  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 213.2° C./.(COOH).sub.2               29  10  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.4                                                                  mp. 210.1° C./.(COOH).sub.2               30  10  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.2                                                                  mp. 204.1° C./.(COOH).sub.2               31  10  CHCHCHCH     (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 227.6° C./.(COOH).sub.2               32  10  (CH.sub.2).sub.4                                                                           (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 229.9° C./.(COOH).sub.2               33  10  OCHCH        (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 223.3° C./.(COOH).sub.2               34  10  O(CH.sub.2).sub.3                                                                          (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 206.6° C./.(COOH).sub.2                8  11  O(CH.sub.2).sub.2                                                                          (CH.sub.2).sub.3                                                                  (CH.sub.2).sub.3                                                                  mp. 200.0° C./.(COOH).sub.2               35  10  SCHCH        (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 227.2° C./.(COOH).sub.2               36  10  (CH.sub.2).sub.3 O                                                                         (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 67.8° C.                              37  10  (CH.sub.2).sub.3 O                                                                         (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.3                                                                  mp. 219° C./.(COOH).sub.2                 38  10  C(CH.sub.3)C(CH.sub.3)O                                                                    (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.2                                                                  mp. 87.1° C.                              39  11  (CH.sub.2).sub.2 S(O).sub.2 O                                                              (CH.sub.2).sub.2                                                                  (CH.sub.2).sub.2                                                                  mp. 207.5° C./.(COOH).sub.2               __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR16##                                                                    Co. No.                                                                           Ex. No                                                                            R.sup.3, R.sup.4                                                                           Alk.sup.1                                                                           Alk.sup.2                                                                           Physical data                                __________________________________________________________________________     9  12  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 231.1° C./.3/2(COOH).sub.2        40  12  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.4                                                                    mp. 193.7° C./.2(COOH).sub.2          41  12  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.2                                                                    mp. 213.5° C./.2(COOH).sub.2          42  12  CHCHCHCH     (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 221.3° C./.2(COOH).sub.2          43  12  (CH.sub.2).sub.4                                                                           (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 205.6° C./.2(COOH).sub.2          44  12  O(CH.sub.2).sub.3                                                                          (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 230.8° C./.3/2(COOH).sub.2        45  12  OCHCH        (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    2(COOH).sub.2                                46  12  O(CH.sub.2).sub.2 O                                                                        (CH.sub.2).sub.3                                                                    (CH.sub.2).sub.3                                                                    mp. 205.5° C./.2(COOH).sub.2          47  12  (CH.sub.2).sub.3 O                                                                         (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 191.1° C./.2(COOH).sub.2          48  12  C(CH.sub.3)C(CH.sub.3)O                                                                    (CH.sub.2).sub.2                                                                    (CH.sub.2).sub.3                                                                    mp. 194.0° C./.2(COOH).sub.2          __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     ##STR17##                                                                    Co. No.                                                                           Ex. No.                                                                           R.sup.3, R.sup.4                                                                        Q          physical data                                    __________________________________________________________________________    10  13  O(CH.sub.2).sub.2 O                                                                      ##STR18## mp. 181.1° C./.2(COOH).sub.2              11  14  O(CH.sub.2).sub.2 O                                                                      ##STR19## mp. 155.0° C./.2HCl                       __________________________________________________________________________

C. Pharmacological Example Example 15

Segments of basilar arteries taken from pigs (anaesthetised with sodiumpentobarbital) were mounted for recording of isometric tension in organbaths. The preparations were bathed in Krebs - Henseleit solution. Thesolution was kept at 37° C. and gassed with a mixture of 95% O₂ --5%CO₂. The preparations were stretched until a stable basal tension of 2grams was obtained.

The preparations were made to constrict with serotonin (3×10⁻⁷ M ). Theresponse to the addition of serotonin was measured and subsequently theserotonin was washed away. This procedure was repeated until stableresponses were obtained. Subsequently the test compound was administeredto the organ bath and the constriction of the preparation was measured.This constrictive response was expressed as a percentage of the responseto serotonin as measured previously. The lowest active concentration wasdefined as the concentration at which 50% of the response to serotoninis obtained.

In table 7 the lowest active concentration of compounds of formula (I)are presented.

                  TABLE 7                                                         ______________________________________                                        Co. No.   lowest active concentration (M)                                     ______________________________________                                         1        1 · 10.sup.-6                                               2        3 · 10.sup.-7                                               4        1 · 10.sup.-6                                               6        1 · 10.sup.-6                                               7        3 · 10.sup.-7                                               9        3 · 10.sup.-8                                              10        3 · 10.sup.-7                                              11        1 · 10.sup.-7                                              16        1 · 10.sup.-7                                              17        1 · 10.sup.-6                                              18        1 · 10.sup.-6                                              19        1 · 10.sup.-6                                              20        1 · 10.sup.-7                                              21        1 · 10.sup.-6                                              22        1 · 10.sup.-6                                              23        3 · 10.sup.-7                                              25        1 · 10.sup.-6                                              26        3 · 10.sup.-7                                              27        1 · 10.sup.-7                                              29        1 · 10.sup.-6                                              31        3 · 10.sup.-8                                              32        3 · 10.sup.-7                                              35        3 · 10.sup.-7                                              36        3 · 10.sup.-8                                              38        1 · 10.sup.-6                                              39        1 · 10.sup.-6                                              40        3 · 10.sup.-6                                              44        1 · 10.sup.-6                                              45        3 · 10.sup.-7                                              47        1 · 10.sup.-7                                              48        1 · 10.sup.-6                                              ______________________________________                                    

D. Composition examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

Example 16 Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°˜80° C. After cooling to30°˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I.. The resulting solution was filled into suitable containers.

Example 17 Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

Example 18 Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

Example 19 Film-Coated Tablets Preparation of Table Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

Example 20 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of theA.I.. The solution was cooled to room temperature and supplemented withwater for injection q.s. ad 1 l, giving a solution comprising 4 mg/ml ofA.I.. The solution was sterilized by filtration (U.S.P. XVII p. 811) andfilled in sterile containers.

Example 21 Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

Example 22 Injectable Solution

60 Grams of A.I. and 12 grams of benzylalcohol were mixed well andsesame oil was added q.s. ad 1 l, giving a solution comprising 60 mg/mlof A.I. The solution was sterilized and filled in sterile containers.

We claim:
 1. A compound of the formula: ##STR20## the pharmaceuticallyacceptable acid addition salts thereof, and the stereochemicallyisomeric forms thereof, wherein:R¹ and R² each independently arehydrogen or C₁₋₆ alkyl; R³ is C₁₋₆ alkyl, hydroxy, cyano, halo, C₁₋₆alkyloxy, aryloxy, arylmethoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkyl-S--, C₁₋₆ alkyl(S═O)--, C₁₋₆ alkylcarbonyl; R⁴ is hydrogen, halo,hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkyloxy;or R³ and R⁴ taken together form abivalent radical of the formula: ##STR21## wherein: in the bivalentradicals (a) through (j) one or two hydrogen atoms may be substitutedwith C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--; each Xindependently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--, --NR⁸ --;n is 3 or 4; each Y independently is --O--, --S--, --S(O)--, --S(O)₂ --,--C(O)--, --NR⁸ --; m is 2 or 3;each Z independently is --O--C(O)--,--C(O)--O--, --NH--C(O)--, --C(O)--NH--, --O--S(O)₂ --; t is 1 or 2; andR⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--; R⁵and R⁶ each independently are hydrogen, halo, hydroxy, C₁₋₆ alkyl, C₁₋₆alkyloxy, aryloxy or arylmethoxy; R⁷ is hydrogen; Alk¹ is C₂₋₅alkanediyl; Alk² is C₂₋₁₅ alkanediyl; and Q is a radical selected fromthe group consisting of radicals of the formula: ##STR22## wherein: R¹²,R¹³, R²⁶ and R²⁷ each independently are hydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆ alkyloxy, aryloxy, C₁₋₆ alkylthio, cyano, amino, mono- ordi(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆ cycloalkyl)amino, aminocarbonyl,C₁₋₆ alkyloxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, piperidinyl,pyrrolidinyl; R¹⁸ and R³⁵ each independently are hydrogen, C₁₋₆ alkyl,C₁₋₆ alkylcarbonyl, or arylC₁₋₆ alkyl; R¹⁶ and R¹⁷ are both hydrogen, ortaken together with the carbon atom to which they are connected formC(O); R³³ is hydrogen and R³⁴ is hydroxy; or R³³ and R³⁴ taken togethermay form a bivalent radical of formula (CH₂)₃ or (CH₂)₄ which isoptionally substituted with C₁₋₆ alkyl; and aryl is phenyl optionallysubstituted with hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy; with theproviso that the compounds of formula (I) wherein R³ is methoxy, ethoxyor isopropyl; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is chloro, fluoro ormethyl; R⁷ is hydrogen; R² is hydrogen or methyl; R¹ is hydrogen; Alk¹is 1,2-ethanediyl or 1,3-propanediyl; Alk² is 1,2-ethanediyl or1,3-propanediyl; and Q is a radical of formula (bb) wherein R¹² ishydrogen and R¹³ is 4-aminocarbonyl, are excluded.
 2. A compound asclaimed in claim 1 wherein R³ is C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy,aryloxy, arylmethoxy, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; one of R⁴, R⁵ andR⁶ is hydrogen and the others each independently are hydrogen, halo,hydroxy, C₁₋₆ alkyl or C₁₋₆ alkyloxy; and Q is a radical of formula(bb), (dd) or (ii).
 3. A compound as claimed in claim 1 wherein R³ andR⁴ taken together form a bivalent radical of the formula: ##STR23##wherein in these bivalent radicals one or two hydrogen atoms may besubstituted with C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkylsulfoxyl;X, Y, Z, m and n are as defined in claim 1; in the bivalent radicals (g)and (h) t is 2; and Q is a radical of formula (bb), (dd) or (ii).
 4. Acompound as claimed in claim 1 wherein R¹ and R² are hydrogen.
 5. Acompound according to claim 1, wherein the compound is N-2-(2,3-dimethoxyphenoxy)ethyl!-N'-2-pyrimidinyl-1,3-propanediamine; 2-2- 3-(2-pyrimidinylamino)propyl!amino!ethoxy!phenol; N-2-(2,3-dimethoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-2-(2-methoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-2-(2-ethoxyphenoxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-3-(2-methoxyphenoxy)propyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!-ethyl!-N'-2-pyrimidinyl-1,3-propanediamine;N- 2-(2,3-dihydro-1,4-benzodioxin-5yl)-oxy!ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N- 2-(2,3-dihydro-1,4-benzodioxin-5-yl)oxy!ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,4-butanediamine;N- 2-(1-naphthalenyloxy)ethyl!-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine,a pharmaceutically acceptable acid addition salt thereof or astereochemically isomeric forms thereof.
 6. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and as an activeingredient a therapeutically effective amount of a compound as claimedin claim
 1. 7. A method for inducing vasoconstriction which comprisesadministering to a patient in need of the same an effectivevasoconstriction amount of a compound of the formula: ##STR24## thepharmaceutically acceptable acid addition salts thereof, and thestereochemically isomeric forms thereof, wherein:R¹ and R² eachindependently are hydrogen or C₁₋₆ alkyl; R³ is C₁₋₆ alkyl, hydroxy,cyano, halo, C₁₋₆ alkyloxy, aryloxy, arylmethoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkyl-S--, C₁₋₆ alkyl (S═O)--, C₁₋₆ alkylcarbonyl; R⁴ ishydrogen, halo, hydroxy, C₁₋₆ alkyl, or C₁₋₆ alkyloxy;or R³ and R⁴ takentogether form a bivalent radical of the formula: ##STR25## wherein: inthe bivalent radicals (a) through (j) one or two hydrogen atoms may besubstituted with C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--;each X independently is --O--, --S--, --S(O)--, --S(O)₂, --C(O)--, --NR⁸--; n is 3 or 4; each Y independently is --O--, --S--, --S(O)--, --S(O)₂--, --C(O)--, --NR⁸ --; m is 2 or 3; each Z independently is--O--C(O)--, --C(O)--O--, --NH--C(O)--, --C(O)--NH--, --O--S(O)₂ --; tis 1 or 2; and R⁸ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆alkyl-S(O)--; R⁵ and R⁶ each independently are hydrogen, halo, hydroxy,C₁₋₆ alkyl, C₁₋₆ alkyloxy, aryloxy or arylmethoxy; R⁷ is hydrogen; Alk¹is C₂₋₅ alkanediyl; Alk² is C₂₋₁₅ alkanediyl; and Q is a radicalselected from the group consisting of radicals of the formula: ##STR26##wherein: R¹², R¹³, R²⁶ and R²⁷ each independently are hydrogen, hydroxy,halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy, aryloxy, C₁₋₆ alkylthio, cyano, amino,mono- or di(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆ cycloalkyl)amino,aminocarbonyl, C₁₋₆ alkyloxycarbonylamino, C₁₋₆ alkylaminocarbonylamino,piperidinyl, pyrrolidinyl; R¹⁸ and R³⁵ each independently are hydrogen,C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, or arylC₁₋₆ alkyl; R¹⁶ and R¹⁷ are bothhydrogen, or taken together with the carbon atom to which they areconnected form C(O); R³³ is hydrogen and R³⁴ is hydroxy;or R³³ and R³⁴taken together may form a bivalent radical of formula (CH₂)₃ or (CH₂)₄which is optionally substituted with C₁₋₆ alkyl; and aryl is phenyloptionally substituted with hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy. 8.The method of claim 7 wherein said method comprises a method fortreating migraine.
 9. The method of claim 7 wherein said methodcomprises a method for treating hypotension.
 10. The method of claim 7wherein said method comprises a method for treating venousinsufficiency.